RESUMO
OBJECTIVE: Screening Chinese angelica (CHA) and Fructus aurantii (FRA) for ingredients with therapeutic effects on colorectal cancer (CRC) and discovering novel targets for the prevention or treatment of CRC. METHODS: TCMSP database as a starting point for the initial selection of ingredients and targets, we screened and validated the ingredients and targets of CHA and FRA using tools such as Autodock Vina, R 4.2.0, and GROMACS. To obtain the pharmacokinetic information of the active ingredients, we performed ADMET prediction and consulted a large number of works related to CRC cell lines for the discussion and validation of the results. RESULTS: Molecular dynamics simulation results showed the complexes formed between these components and targets can exist in a very stable tertiary structure under the human environment, and their side effects can be ignored. CONCLUSIONS: Our study successfully explains the effective mechanism of CHA and FRA for improving CRC while predicting the potential targets PPARG, AKT1, RXRA, and PPARA of CHA and FRA for CRC treatment, which provides a new foundation for investigating the novel compounds of TCMs and a new direction for subsequent CRC research.
Assuntos
Citrus , Neoplasias Colorretais , Medicamentos de Ervas Chinesas , Humanos , Neoplasias Colorretais/tratamento farmacológico , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/farmacologia , Frutas , Simulação de Acoplamento Molecular , Simulação de Dinâmica MolecularRESUMO
Sepsis is a life-threatening condition in which the immune response is directed towards the host tissues, causing organ failure. Since sepsis does not present with specific symptoms, its diagnosis is often delayed. The lack of diagnostic accuracy results in a non-specific diagnosis, and to date, a standard diagnostic test to detect sepsis in patients remains lacking. Therefore, it is vital to identify sepsis-related diagnostic genes. This study aimed to conduct an integrated analysis to assess the immune scores of samples from patients diagnosed with sepsis and normal samples, followed by weighted gene co-expression network analysis (WGCNA) to identify immune infiltration-related genes and potential transcriptome markers in sepsis. Furthermore, gene regulatory networks were established to screen diagnostic markers for sepsis based on the protein-protein interaction networks involving these immune infiltration-related genes. Moreover, we integrated WGCNA with the support vector machine (SVM) algorithm to build a diagnostic model for sepsis. Results showed that the immune score was significantly lower in the samples from patients with sepsis than in normal samples. A total of 328 and 333 genes were positively and negatively correlated with the immune score, respectively. Using the MCODE plugin in Cytoscape, we identified four modules, and through functional annotation, we found that these modules were related to the immune response. Gene Ontology functional enrichment analysis showed that the identified genes were associated with functions such as neutrophil degranulation, neutrophil activation in the immune response, neutrophil activation, and neutrophil-mediated immunity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed the enrichment of pathways such as primary immunodeficiency, Th1- and Th2-cell differentiation, T-cell receptor signaling pathway, and natural killer cell-mediated cytotoxicity. Finally, we identified a four-gene signature, containing the hub genes LCK, CCL5, ITGAM, and MMP9, and established a model that could be used to diagnose patients with sepsis.
Assuntos
Sepse , Máquina de Vetores de Suporte , Algoritmos , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Sepse/diagnóstico , Sepse/genéticaRESUMO
BACKGROUND: Recent research underscores the pivotal role of immune checkpoints as biomarkers in colorectal cancer (CRC) therapy, highlighting the dynamics of resistance and response to immune checkpoint inhibitors. The impact of epigenetic alterations in CRC, particularly in relation to immune therapy resistance, is not fully understood. METHODS: We integrated a comprehensive dataset encompassing TCGA-COAD, TCGA-READ, and multiple GEO series (GSE14333, GSE37892, GSE41258), along with key epigenetic datasets (TCGA-COAD, TCGA-READ, GSE77718). Hierarchical clustering, based on Euclidean distance and Ward's method, was applied to 330 primary tumor samples to identify distinct clusters. The immune microenvironment was assessed using MCPcounter. Machine learning algorithms were employed to predict DNA methylation patterns and their functional enrichment, in addition to transcriptome expression analysis. Genomic mutation profiles and treatment response assessments were also conducted. RESULTS: Our analysis delineated a specific tumor cluster with CpG Island (CGI) methylation, termed the Demethylated Phenotype (DMP). DMP was associated with metabolic pathways such as oxidative phosphorylation, implicating increased ATP production efficiency in mitochondria, which contributes to tumor aggressiveness. Furthermore, DMP showed activation of the Myc target pathway, known for tumor immune suppression, and exhibited downregulation in key immune-related pathways, suggesting a tumor microenvironment characterized by diminished immunity and increased fibroblast infiltration. Six potential therapeutic agents-lapatinib, RDEA119, WH.4.023, MG.132, PD.0325901, and AZ628-were identified as effective for the DMP subtype. CONCLUSION: This study unveils a novel epigenetic phenotype in CRC linked to resistance against immune checkpoint inhibitors, presenting a significant step toward personalized medicine by suggesting epigenetic classifications as a means to identify ideal candidates for immunotherapy in CRC. Our findings also highlight potential therapeutic agents for the DMP subtype, offering new avenues for tailored CRC treatment strategies.